The present invention relates to 3-hydroxymethyl-benzo[b]thiophene derivatives which are important as starting materials for the production of compounds useful in the pharmaceutical field, and methods for producing them.
3-Hydroxymethyl-benzo[b]thiophene derivatives represented by the formula (II): 
wherein, R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group, are very important as intermediates for the production of pharmacologically active compounds.
For example, a compound in which a hydroxyl group has been replaced with a bromine atom in a compound represented by the formula (II) can be a starting material for a synthetic intermediate of benzimidazole derivatives described in the specification of WO 01/53291, and can be said to be very important as an intermediate for the production of pharmacologically active compounds.
However, the production of benzothiophene derivatives having a hydroxymethyl group at the position 3 and having other substituents in a position-selective manner as in the compounds represented by the formula (II) is very difficult, and none have been suitable for industrial production. For example, there are a method in which benzo[b]thiophene is subjected to the Vilsmeier reaction etc. to synthesize 3-formyl-benzo[b]thiophene (J. Org. Chem., 72:1422 (1957)) which is then reduced, a method in which benzo[b]thiophene is subjected to the Friedel-Crafts reaction to synthesize a 3-trichloroacetyl-benzo[b]thiophene derivative (J. Chem. Soc., Perkin Trans. 2:1250 (197u3)) as a starting material candidate, which is hydrolyzed and then reduced, and the like. In any of them, however, depending on the type and the position of the originally retained substituents, at both positions 2 and 3 or any position from positions 2 to 7 on the benzo[b]thiophene ring, a substitution reaction proceeds wherein position-selectivity in the reaction highly tends to depend on the substrates and the reaction conditions used, and thus selectivity is not always high. Furthermore, the isolation of the desired compound from these mixtures is very difficult.
Furthermore, J. Chem. Soc., Chem. Comm., 848 (1974) reports a reaction in which, a propargyl group was introduced into a benzenethiol derivative, which is then subjected to an oxidation reaction to obtain a compound represented by the formula (VIII): 
wherein R6 and R7 are all hydrogen atoms, or R6 and R7 together form a benzene ring, which is then subjected to a heat transfer reaction to obtain a compound represented by the formula (IX): 
wherein R6 and R7 are all hydrogen atoms, or R6 and R7 together form a benzene ring, which is then subjected to a heat transfer reaction in water-dioxane in the presence of p-toluenesulfonic acid to obtain a compound represented by the formula (X): 
wherein R6 and R7 are all hydrogen atoms, or R6 and R7 together form a benzene ring. In this reaction, however, reaction may occur at both ortho positions of the sulfur atom in the compound represented by the formula (VIII), and thus, depending on the position of substituents on the benzene ring, the selectivity required to obtain the compound of interest may not be obtained. Thus, there may be formed the formula (XI) which is not desired, together with the formula (IX), and the formula (XII) which is not desired, together with the formula (X). 
wherein R6 and R7 are all hydrogen atoms, or R6 and R7 together form a benzene ring.
From the foregoing, there has been a need for a selective method of synthesizing 3-hydroxymethyl-benzo[b]thiophene represented by the formula (II) without the possible concomitant production of isomers.
It is an object of the present invention to resolve the problems encountered in the above conventional methods, and to provide a method of producing 3-hydroxymethyl-benzo[b]thiophene derivatives without the possible concomitant production of isomers.
The present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the formula (II): 
wherein, R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group, by allowing a hydrogenating agent to act on a compound represented by the formula (I): 
wherein, R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, thereby to attain the selective hydrogenation of the substituent X alone.
In the above method, it is preferred that R1 to R3 in the above formula (I) are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, or a trihalomethyl group, and X is a halogen atom.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the above formula (II), wherein a benzo[b]thiophene derivative represented by the above formula (I) is produced by reducing a compound represented by the formula (IV): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons; and R4 is an acyl group, with a hydrogenating metal complex compound, basic hydrolysis, or acid hydrolysis.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the above formula (II), wherein a benzo[b]thiophene derivative represented by the above formula (IV) is produced by reacting a compound represented by the formula (III): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, with one or more of carboxylic acid anhydride or carboxylic acid.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the above formula (II), wherein a compound represented by the above formula (III) is produced by the following steps (1) to (3):
(1) a step of reacting a propargyl group to a compound represented by the formula (V): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons; and R5 is an alkoxythiocarbonyl group, an alkyl group, a hydrogen atom, a halogen atom, a sodium atom, a lithium atom, a potassium atom, a magnesium atom, or a calcium atom, in a substitution reaction to obtain a compound represented by the formula (VI): 
wherein R1 to R3 and X are as defined in the above formula (V);
(2) a step of oxidizing a compound represented by the formula (VI) to obtain a compound represented by the formula (VII): 
wherein R1 to R3 and X are as defined in the above formula (V); and
(3) a step of obtaining a compound represented by the formula (III) by subjecting a compound represented by the above formula (VII) to a heat transfer reaction.
Furthermore, the present invention provides a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the formula (II): 
wherein R1 and R2 are, same or independently, an alkyl group having 1 to 4 carbons, and R3 is a hydrogen atom.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the formula (I): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, characterized in that a compound represented by the formula (IV): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons; and R4 is an acyl group, is reduced with a hydrogenating metal complex compound, basic hydrolysis, or acid hydrolysis.
Furthermore, the present invention provides a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the formula (I): 
wherein R1 is an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; R2 and R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom.
In the above formula (I), a 3-hydroxymethyl-benzo[b]thiophene derivative
wherein X is a halogen atom, R1 is an alkyl group having 1 to 4 carbons, and each of R2 and R3 is a hydrogen atom; or
X is a halogen atom, R1 and R2 are, together or independently, an alkyl group having 1 to 4 carbons, and R3 is a hydrogen atom, is preferable.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the formula (IV): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons; and R4 is an acyl group, by reacting a compound represented by the formula (III): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, with one or more of carboxylic acid anhydride or carboxylic acid.
In said method of production, preferably, R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, or a trihalomethyl group; and X is a halogen atom in the above formula (III).
Furthermore, the present invention provides a benzo[b]thiophene derivative represented by the formula (IV): 
wherein X is a halogen atom, R4 is a trifluoroacetyl group, and R1 is an alkyl group having 1 to 4 carbons, R2 and R3 are a hydrogen atom, or R1 and R2 are, together or independently, an alkyl group having 1 to 4 carbons, and R3 is a hydrogen atom.
In accordance with the present invention, it is preferred that a compound represented by the formula (III): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, is reacted with one or more of carboxylic acid anhydride or carboxylic acid to obtain a compound represented by the formula (IV): 
wherein R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons; and R4 is an acyl group,
R4 of the compound (IV) is replaced with a hydroxyl group to obtain a compound represented by the formula (I): 
wherein, R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, and then
the substituent X of a compound represented by the formula (I) is subjected to a selective hydrogen-substitution reaction to produce a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the formula (II): 
wherein, R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group.
R1 to R3 in the formula of the present invention are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group. Preferably, R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, a halogen atom, and most preferably a hydrogen atom or an alkyl group having 1 to 4 carbons
R4 in the formula is an acyl group. R4 is preferably a trifluoroacetyl group or an acetyl group, and more preferably a trifluoroacetyl group.
X in the formula is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons. X is preferably a bromine atom or a chlorine atom, and more preferably a bromine atom.
In preferred combinations of R1, R2 and R3, R1 and R3 are not the same. In more preferred combinations of R1, R2 and R3, R1 is an alkyl group having 1 to 4 carbons, R2 and R3 are a hydrogen atom, or R1 and R2 are an alkyl group having 1 to 4 carbons and R3 is a hydrogen atom. In more preferred combinations of R1, R2 and R3, R1 is a methyl group or an ethyl group, and R2 and R3 are a hydrogen atom; or R1 and R2 are a methyl group or an ethyl group, and R3 is a hydrogen atom. In particularly more preferred combinations of R1, R2 and R3, R1 is a methyl group and R2 and R3 are a hydrogen atom.
As examples of preferred combinations of R1, R2 and R3, the following are specifically illustrated.
Preferred compounds of compound (III) are 7-bromo-4-methyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol, 7-chloro-4-methyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol, 7-bromo-4,5-dimethyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol, 7-chloro-4,5-dimethyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol, 7-bromo-4-ethyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol, and 7-chloro-4-ethyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol. More preferably, they are 7-bromo-4-methyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol and 7-chloro-4-methyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol. A more preferred compound (III) is 7-bromo-4-methyl-3-methylene-2-hydro-benzo[b]thiophene-2-ol.
Preferred compounds of compound (IV) are (7-bromo-4-methylbenzo[b]thiophene-3-yl)methyl trifluoroacetate, (7-chloro-4-methylbenzo[b]thiophene-3-yl)methyl trifluoroacetate, (7-bromo-4,5-dimethylbenzo[b]thiophene-3-yl)methyl trifluoroacetate, (7-chloro-4,5-dimethylbenzo[b]thiophene-3-yl)methyl trifluoroacetate, (7-bromo-4-ethylbenzo[b]thiophene-3-yl)methyl trifluoroacetate, and (7-chloro-4-ethylbenzo[b]thiophene-3-yl)methyl trifluoroacetate. More preferred compounds (IV) are (7-bromo-4-methylbenzo[b]thiophene-3-yl)methyl trifluoroacetate and (7-chloro-4-methylbenzo[b]thiophene-3-yl)methyl trifluoroacetate. A most preferred compound (IV) is (7-bromo-4-methylbenzo[b]thiophene-3-yl)methyl trifluoroacetate.
Preferred compounds of compound (I) are 7-bromo-3-hydroxymethyl-4-methyl-benzo[b]thiophene, 7-chloro-3-hydroxymethyl-4-methyl-benzo[b]thiophene, 7-bromo-3-hydroxymethyl-4,5-dimethyl-benzo[b]thiophene, 7-chloro-3-hydroxymethyl-4,5-dimethyl-benzo[b]thiophene, 7-bromo-3-hydroxymethyl-4-ethyl-benzo[b]thiophene, and 7-chloro-3-hydroxymethyl-4-ethyl-benzo[b]thiophene, and preferred compounds of compound (II) are 3-hydroxymethyl-4-methylbenzo[b]thiophene, 3-hydroxymethyl-4-ethylbenzo[b]thiophene, and 3-hydroxymethyl-4,5-dimethylbenzo[b]thiophene. More preferred compounds of compound (I) are 7-bromo-3-hydroxymethyl-4-methyl-benzo[b]thiophene and 7-chloro-3-hydroxymethyl-4-methyl-benzo[b]thiophene. A particularly more preferred compound of compound (I) is 7-bromo-3-hydroxymethyl-4-methyl-benzo[b]thiophene.
In the hydrogen substitution reaction from formula (I) to (II) in the present invention, the reaction is effected with sodium hydrogenated bis(2-methoxyethoxy)aluminum, lithium aluminum hydride, hydrogen/palladium carbon/magnesium, hydrogen/palladium carbon/triethylamine, hydrogen/palladium carbon-ethylenediamine complex/triethylamine, and the like. In preferred methods, reaction is effected with sodium hydrogenated bis(2-methoxyethoxy)aluminum, lithium aluminum hydride, and hydrogen/palladium carbon/triethylamine.
Solvents for use in the hydrogen substitution reaction from formula (I) to (II) preferably include, but not limited to, toluene, THF, diethylether, methanol, ethanol, isopropyl alcohol, and the like.
The reaction temperature in the reaction from formula (I) to formula (II) of the present invention is carried out preferably at 0xc2x0 C. to 80xc2x0 C.
Particularly preferred conditions include a reaction of a compound (I) and a four-fold amount of hydrogenated bis(2-methoxyethoxy)aluminum in a molar ratio relative to the compound (I) in toluene-THF at 70xc2x0 C. for 3 hours; a reaction of a compound (I) and a four-fold amount of lithium aluminum hydride in a molar ratio relative to the compound (I) in THF at 70xc2x0 C. for 36 hours; or a reaction of a compound (I) and a 0.10-fold amount of palladium carbon in a molar ratio relative to the compound (I), and a 1.2-fold amount of triethylamine in a molar ratio relative to the compound (I) in a methanol solvent at a hydrogen atmosphere at 50xc2x0 C. for 24 hours.
Methods of synthesizing compounds represented by the formula (I) of the present invention include, but not limited to, those methods mentioned below. It should be noted, however, that the following reaction conditions differ with the properties of the substrates used and hence are not limited to the following conditions in any way. 
The definition of R1, R2, R3, R4, R5 and X used in the above scheme are as described below. R1 to R3 are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; R4 is an acyl group; R5 is an alkoxythiocarbonyl group, an alkyl group, a hydrogen atom, a halogen atom, a sodium atom, a lithium atom, a potassium atom, a magnesium atom, or a calcium atom; and X is a halogen atom, a hydroxy atom, or an acyloxy group having 1 to 9 carbons.
The steps represented by 1 to 8 in the above scheme are now explained in detail.
(Step 1)
In this step, the nitro group in the substituted nitrobenzene (XIII) is selectively reduced to produce a compound represented by the formula (XIV). The reaction of this step can be accomplished by stirring hydrochloric acid and tin dichloride in acetic acid at room temperature to 60xc2x0 C. for 8 to 12 hours. The reaction of this step can also be accomplished by stirring in the presence of hydrazine monohydrate and the Raney Nickel catalyst in a solvent such as methanol, ethanol or THF at room temperature to the reflux temperature for 8 to 12 hours. The reaction of this step can also be accomplished by stirring in the presence of a platinum carbon catalyst in formic acid and triethylamine at 100xc2x0 C. for 3 to 12 hours.
(Step 2)
In this step, the substituted aniline (XIV) is converted to a diazonium salt, to which various alkoxydithiocarbonates or thiolate are reacted to obtain a benzenethiol derivative (V). It is reacted as an aqueous solution of hydrochloric acid with sodium nitrite at the range of 0-10xc2x0 C. to convert the substituted aniline to a diazonium salt. The method of changing the diazonium into alkoxy dithio carbonate preferably uses potassium O-ethyldithio carbonate, and the reaction temperature is 40xc2x0 C. to 50xc2x0 C., preferably 45xc2x0 C. to 50xc2x0 C. for 1 to 2 hours.
(Step 3)
In this step, in stead of the alkoxycarbonyl of the benzenethiol derivative (V), a propargyl group is subjected to a substitution reaction to obtain a compound represented by the formula (VI). The introduction of the propargyl group can be accomplished with a halogenated propargyl, for example propargyl bromide or propargyl chloride using a basic substance such as N,N-dimethylethylenediamine, ethylenediamine, 2-aminoethylmorpholine, or methylamine in a solvent such as acetone, tetrahydrofuran, 2-butanone, methanol, ethanol or isopropyl alcohol at xe2x88x9220xc2x0 C. to 30xc2x0 C. in 1 to 2 hours.
(Step 4)
In this step, a sulfide derivative (VI) is oxidized to a sulfoxide derivative (VII). In this step, preferably 1.05 equivalent of Oxone, and 0.1 equivalent of acetone, a 0.05 equivalent of phase-transfer catalyst such as tetrabutyl ammonium bromide or tetrabutyl ammonium chloride are stirred in the solvent system of ethyl acetate-water at 0xc2x0 C. to 30xc2x0 C. for 6 hours to 25 hours. In this step also, 1.2 equivalent of sodium metaperiodate is stirred in the solvent system of alcohol (e.g. methanol, ethanol, or isopropanol)-water at room temperature for several hours.
(Step 5)
In this step, a compound represented by the formula (III) is synthesized by a transfer cyclization reaction of a sulfoxide derivative (VII). For the transfer cyclization reaction of the present invention, reference is made to the method described in J.C.S. Chem. Comm., 848-849, 1974. For the sulfoxide for use in the present invention, preferred solvents include ethyl acetate, propyl acetate, isopropyl acetate, dimethoxyethane, 2-butanone, dioxane and the like. Preferably the amount of the solvent required is, but not limited to, more than 10 times the weight of the substrate, more preferably 15 to 25 times the weight of the substrate. By reacting this amount of the solvent, the production of byproducts can be suppressed at the minimum level and the yield can thus be enhanced. The reaction is preferably carried out at the reaction temperature of 60xc2x0 C. to 100xc2x0 C., and preferably 80xc2x0 C. to 90xc2x0 C. When the reaction is carried out at the reflux temperature, it will be complete in 30 minutes to 3 hours.
(Step 6)
In this step, the cyclized product (III) obtained in step 5 is reacted to a carboxylic acid anhydride or carboxylic acid to produce a compound represented by the formula (IV).
The solvent used in this step is the reaction solvent used in step 5, but without being concentrated, and to the reaction system a carboxylic acid anhydride or a carboxylic acid is merely added thereby to obtain a 3-alkylcarbonylmethylbenzo[b]thiophene derivative or a 3-hydroxymethylbenzo[b]thiophene derivative. A similar reaction will proceed when the solvent in step 5 is concentrated and is reacted in a different solvent. The carboxylic acid anhydride or the carboxylic acid to be added in this reaction is one or more than one, and as the carboxylic acid anhydride trifluoroacetic acid anhydride or acetic anhydride is preferred, and as carboxylic acid trifluoroacetic acid anhydride or acetic acid is preferred.
The reaction temperature in this reaction is 0xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. The reaction will be complete in scores of minutes to several hours.
(Step 7)
In this step, the carboxylic acid ester, if obtained in step 6, is hydrolyzed to obtain a 3-hydroxymethyl-benzo[b]thiophene derivative (I). The reaction is carried out using tetrahydrofuran, methanol, ethanol, or isopropyl alcohol as the solvent, and to the carboxylic acid ester an aqueous solution of sodium hydroxide or sodium borohydride is reacted. The reaction will be complete at a temperature of 0xc2x0 C. to 30xc2x0 C. in several hours. As the reaction solvent, tetrahydrofuran-methanol may be mentioned.
(Step 8)
In this step, a compound represented by the formula (II) is produced by the hydrogenation reaction of position 7 of 3-hydroxymethyl-benzo[b]thiophene derivative (I).
The hydrogenating agent used is sodium hydrogenated bis(2-methoxyethoxy)aluminum, lithium aluminum hydride, hydrogen/palladium carbon/magnesium, hydrogen/palladium carbon/triethylamine, hydrogen/palladium carbon-ethylenediamine complex/triethylamine, or the like. Preferred are sodium hydrogenated bis(2-methoxyethoxy)aluminum, lithium aluminum hydride, or hydrogen/palladium carbon/triethylamine.
The solvent for use in this step preferably includes, but not limited to, toluene, THF, diethylether, methanol, ethanol, isopropyl alcohol or the like. The reaction of this step may preferably be carried out at a temperature of 0xc2x0 C. to 80xc2x0 C.
By replacing, with a bromine atom, the hydroxy group of 3-hydroxymethyl-benzo[b]thiophene derivative of the formula (II) produced in the above method, a 3-bromomethyl-benzo[b]thiophene derivative can be synthesized. The condition of the substitution reaction from the hydroxy group to the bromine atom is preferably, but not limited to, a reaction using a known phosphorus tribromide. By using the bromo product obtained, a benzimidazole derivative useful as a pharmaceutical composition may be synthesized according to a method described in, for example, WO01/53291.